Synapses are specialized junctions through which cells of the nervous system signal to one another and to non-neuronal cells such as muscle or gland cells. A cell sending a signal is referred to as a pre-synaptic cell and a cell receiving a signal as a post-synaptic cell. Synapses can be electrical or chemical. Chemical synapses are more common and are much wider, typically 20 to 40 nm.
An electrical synapse is a reciprocal, mechanical, and electrically conductive link between two neurons that forms at a narrow gap between the pre- and post-synaptic cells. Electrical synapses are also called gap junctions. A gap junction is formed by many intercellular protein complexes or junctional channels that directly connect the cytoplasm between adjacent cells. The intercellular protein complex may differ among the gap junctions formed by different types of neurons. Typically, gap junctions are about 3.5 nm across and allow direct transmission of signals (including chemical and electrical signals) between neurons. Through a gap junction, molecules and ions can freely pass between the connected cells. Unlike chemical synapses, electrical synapses do not need receptors to recognize chemical messengers, thus signaling across electrical synapses is faster than that which occurs across chemical synapses. Because of the speed of transmission, electrical synapses occur in escape mechanisms and other processes that require quick responses.
It has been revealed that synchronization of neuronal activity is the most important and primary function of gap junctions in the mammalian central nervous system (Bennett, M. V. & Zukin, R. S., Neuron 41, 495-511 (2004); Galarreta, M. & Hestrin, S., Nat Rev Neurosci 2, 425-33 (2001); Connors, B. W. & Long, M. A., Annu Rev Neurosci 27, 393-418 (2004); Cruikshank, S. J., et al., Prog Brain Res 149, 41-57 (2005)). The mammalian neocortex and hippocampus often generate synchronized, rhythmic patterns of activity that vary with behavioral states. Synchronized neuronal activity can exhibit a fast waveform (4-12 Hz for θ frequencies and 20-70 Hz for y frequencies) or an ultrafast waveform (called “ripple” oscillations in the range of 100-600 Hz).
Pyramidal cells are large, pyramid-shaped excitatory neurons found in the hippocampus and cerebral cortex. Gap junctions between pyramid cells are fundamental to the generation of synchronized activity, especially ultrafast frequency synchronizations (Maier, N. et al., J Physiol 541, 521-8 (2002); Hormuzdi, S. G. et al., Neuron 31, 487-95 (2001); Buhl, D. L., et al., J Neurosci 23, 1013-8 (2003)). These ultrafast synchronizations may play a role in neuronal processing in the hippocampal and neocortical areas, such as sensory perception, motor performance, attention, and memory consolidation (Bennett, M. V. & Zukin, R. S., Neuron 41, 495-511 (2004)). Electrophysiological studies have implicated the ultrafast rhythms via pyramidal gap junctions in the generation of pathological hypersynchrony of neuronal activity. Epilepsy seizures are one example of such hypersynchrony (Ponomarenko, A. A., et al., Usp Fiziol Nauk 33, 34-42 (2002); Nyikos, L., et al., Neuroscience 121, 705-17 (2003); Nemani, V. M. & Binder, D. K., Histol Histopathol 20, 253-9 (2005)). Gap junction activity is the synaptic basis for epilepsy seizure.
Gap junction inhibitors have shown powerful anticonvulsant effects, in both in vitro and in vivo studies (Nyikos, L., et al., Neuroscience 121, 705-17 (2003)). Known gap junction inhibitors include octanol, heptanol, carbenoxolone, oleamide, halothane, and 18-α and 18-β-glycyrrhetinic acid. Due to the high frequency of side effects, the use of these compounds is limited and they can be unreliable as therapeutics (Yukari Takeda et al., Am J Physiol Gastrointest Liver Physiol. 288: G832-G841 (2005); Abrahamsson H, and Dotevall G., Scand J Gastroenterol Suppl., 55:117-20 (1979)). What is needed is a method of inhibiting gap junction activity with fewer side effects.